Cell-mediated immune reactions are the basis of autoimmune diseases, and inflammation of tissue plays a part in such diseases. Activation of T cells is a causitive factor in numerous inflammatory diseases, particularly psoriasis (and including: graft rejection, dermatitis, asthma, and rheumatoid arthritis).
T cell activation is the central event in the inflammatory response, which is accompanied by a recruitment of peripheral blood leukocytes to the site of inflammation or injury, leukocyte adhesion to vascular endothelium, and migration from the circulation to sites of inflammation.
T-cell activation is mediated by the T cell receptor (TCR) (A. S. Shaw and M. L. Dustin, Immunity 6: 361 (1997)), whose activation in turn requires engagement of at least two types of T cell surface receptors. A key T cell surface receptor in this process is a member of the CD-11 integrin familyxe2x80x94lymphocyte function associated antigen-1 or LFA-1, (also known as CD11a/CD18), which mediates lymphocyte adhesion and activation leading to normal immune response, as well as to several pathological states (Dustin, M. L., Shaw, A. S., Science 283: 649-650 (1999), Springer, T. A., Nature 346:425-434 (1990)).
LFA-1 binds to certain specific intercellular adhesion molecules (ICAMs) found on endothelium, leukocytes and other cell types. These ICAMs, known as ICAM-1, -2, and -3 are members of the immunoglobulin superfamily. Blocking the binding of ICAM ligands to CD11integrin receptors has been found to inhibit various undesired T-cell dependent immune responses, such as skin graft and bone marrow rejection, and development of diabetes mellitus. For example, anti-CD11a Mabs inhibit T-cell activation (Kuypers et al., Res. Immunol., 140: 461 (1989)), T-cell dependant B-cell proliferation and differentiation (Davignon et al., J. Immunol., 127: 590 (1981)). Such blocking has up till now been performed by antibodies. Thus, antagonists of LFA-1, that is antibodies or other molecules which prevent ICAMs from binding to the LFA-1 receptor but do not themselves activate the receptor, are useful in preventing diseases related to unwanted T-cell activation, such as psoriasis, graft rejection, dermatitis, asthma, and rheumatoid arthritis.
Small molecules are preferable to antibodies for treatment purposes for numerous reasons including increased tissue penetration, reduced immunogenicity, and in general lower risk. This is especially important in treatment of psoriasis. Thus developing small molecule compounds which are LFA-1 antagonists is an important step in combatting psoriasis.
The compounds of this invention are active as LFA-1 antagonists. This activity enables these compounds to prevent the inflammation which is a consequence of T cell activation, and accordingly reduce or eliminate the inflammatory skin disease psoriasis.
This invention is directed to compounds of formulae 1, 1a-1g, 1-1, 1-1a-1-1c, and prodrugs of formulae 2 and 2-1, pharmaceutical compositions containing these compounds, and methods of treating psoriasis with these compounds.
This invention is directed to compounds of formula 1 and formula 1-1: 
R1 is hydrogen, hydroxy, amino or halogen, R2 is hydrogen, hydroxy, or halogen and R3 is hydrogen 
where R1 is hydrogen and R2 and R3 taken together with the ethenylene group connecting them form phenyl, pyrrole, pyrroline, oxopyrroline, pyrazole, triazole, or imidazole. In both formula 1 and formula 1-1, A is one of the following groups, 
R4 and R5 are hydrogen, methyl, ethyl or halogen (except that R4 and R5 cannot both be hydrogen), and B can be selected from any one of the following 7 groups, namely:
1) B is hydrogen, or lower alkyl; or
2) B is 
Here, R6 R7 R8 and R9 are independently hydrogen, hydroxy, aminosulfonyl, halogen, lower alkoxy, cyano, amino, lower alkyl, lower alkyl amino, or nitro; or
3) B is 
Here, R10 is hydrogen, hydroxy, halogen, or lower alkyl and C is a five- or six-membered ring with 0 to 3 heteroatoms which are selected from nitrogen, oxygen, and sulfur. The ring may have no heteroatoms, or up to 3 heteroatoms which can be N, O, and S in any chemically appropriate combination. This ring may be unsubstituted or mono- or di- substituted with lower alkyl, cycloalkyl, amino, or substituted amino; or
4B is 
xe2x80x83where X and Y are independently methylene or nitrogen; or
5) B is 
Here, at least one of T, U, V, or W is nitrogen, and any of T, U, V or W which is carbon may be substituted with lower alkyl, lower alkyl amino, lower alkoxy, hydroxy, aminosulfonyl, halogen, cyano, amino, or nitro, i.e. for any compound of this invention where B is (5), any position (from among T, U, V or W) which is carbon and not nitrogen, may have one of the substituents listed; or 
wherein Y is carbon or nitrogen; or
7) B is a five-membered aromatic ring. The ring may have 1 to 3 heteroatoms which are selected from nitrogen, oxygen, and sulfur (in any chemically appropriate combination). The ring may be unsubstituted or mono- or di- substituted at any position with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, substituted amino. The ring may also be fused with a 5 or 6 membered aromatic ring. The fused ring may contain 0 to 3 heteroatoms which heteroatoms are selected from nitrogen, oxygen, and sulfur (i.e. the fused ring may have no heteroatoms, or up to 3 heteroatoms which can be N, O, and S in any chemically appropriate combination). The ring may in particular be fused with phenyl.
Hereinafter, the groups from which B may be selected will be referred to (for convenience) by number, e.g. (1), (2), (3), (4), (5), (6), and (7)
In any compound of this invention (such as compounds of formulae 1, 1a-1g, 1-1, 1-1a-1-1c, 2, 2-1, and particularly those in the paragraph below) where B is (5), it is preferred that V be nitrogen, i.e. B is 
and T, U, or W are nitrogen or carbon. Any of T, U, or W which is carbon may be substituted with lower alkyl, lower alkyl amino, lower alkoxy, hydroxy, aminosulfonyl, halogen, cyano, amino, or nitro.
In any compound of this invention where B is the five-membered aromatic ring (7), it is preferred that one of the 1 to 3 heteroatoms of the ring be located at a position which is two positions from the attachment point (of the ring to the rest of the molecule depicted for example in formula 1 or 1-1). It is also preferred for any compound of this invention (such as compounds of formulae 1, 1a-1g, 1-1, 1-1a-1-1c, 2, 2-1, and particularly the compound described in this paragraph and those of the above paragraphs) where B is the five-membered aromatic ring (7) and is fused with a five or six membered aromatic ring with 0 to 3 heteroatoms, such as phenyl, that the positions of fusion are not adjacent to the attachment point.
Especially preferred compounds of this invention are compounds of formula 1 where R1 is hydroxy or amino and R2 and R3 are hydrogen and compounds of formula 1-1 where R2 and R3 together with the ethenylene to which they are attached form phenyl, pyrazole or pyrrole. In these compounds, A is 
R4 and R5 are lower alkyl or halogen;
and B is 
xe2x80x83where R11 is hydrogen, lower alkyl, substituted amino, or amino and R12 is hydrogen, trifluoroloweralkyl or lower alkyl. All variants of these compounds are specifically contemplated by this invention. For example, compounds of formula 1 where R1 is hydroxy or amino or compounds of formula 1-1 where R2 and R3 together with the ethenylene to which they are attached form phenyl, pyrazole or pyrrole and A is 
xe2x80x83and B is the benzotriazole, or the same compounds where B is the thiazole, or the quinoline, or the aminosulfonylphenyl, are included.
Similarly compounds of formula 1 or formula 1-1 as above where A is 
and B is the benzotriazole, or the same compound where B is the thiazole, or the quinoline, or the aminosulfonylphenyl, are included. Also part of this invention are such compounds where A is 
It is preferred that R4 and R5 are methyl or halogen. In compounds where B is the thiazole, it is preferred that R11 is hydrogen, methyl, piperazinyl, trifluoromethyl, methyl, or cyclopropyl.
In compounds of formula 1-1 where R2 and R3 together with the ethenylene to which they are attached form phenyl, pyrazole or pyrrole, it is preferred that R2 and R3 together with the ethenylene to which they are attached form pyrazole or pyrrole.
In preferred compounds, R2 and R3 together with the ethenylene to which they are attached form pyrazole or pyrrole, A is 
R4 and R5 are methyl or halogen; and B is 
where R11 is hydrogen, methyl, piperazinyl, isopropyl, or amino and R12 is hydrogen, trifluoromethyl, methyl. Any variant of this compound is contemplated by this invention, as described in the two paragraphs immediately above. In an especially preferred compound, R2 and R3 together with the ethenylene to which they are attached form pyrazole or pyrrole, A is 
and R11 and R12 are methyl.
Certain compounds of formula 1 have the formula 
wherein R4 and R5 are hydrogen, methyl, ethyl or halogen except that they cannot both be hydrogen, and B is selected from options (1), (2), (3), (4), (5), (6), and (7).
In some of these compounds, B is (1). Examples of such compounds are (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]pent-2-enoic acid, 2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid, or 2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid.
In other compounds of formula 1a, B is (2) (i.e. 
where R6, R7, R8 and R9 are independently hydrogen, hydroxy, aminosulfonyl, halogen, alkoxy, cyano, lower alkyl, lower alkyl amino, amino, or nitro), especially hydrogen, hydroxy, aminosulfonyl, or halogen, preferably hydrogen. Examples of such compounds are (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-hydroxyphenyl)propenoic acid,
(Z)-2-[[2-chloro-4-[[-(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(4-sulfamoylphenyl)propenoic acid, and
(Z)-3-(4-bromophenyl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid.
Compounds where R6, R7, R8 and R9 are hydrogen include
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-phenylpropenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-phenylpropenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-phenylpropenoic acid, and (Z)-2-[[4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoyl]amino]-3-phenylpropenoic acid.
Also part of this invention is a compound of formula 1a wherein B is (3) (i.e. 
where R10 is hydrogen, hydroxy, halogen, or lower alkyl and C is a five- or six- membered ring with 0 to 3 heteroatoms, which heteroatoms are selected from nitrogen, oxygen, and sulfur, which ring may be unsubstituted or mono- or di- substituted with lower alkyl, cycloalkyl, or substituted amino). In preferred such compounds, C is a six-membered ring, especially a six-membered ring with 0 heteroatoms (e.g. phenyl). An example of the latter compound is (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]-3-(naphthalen-2-yl)propenoic acid. (A related compound of this invention is (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]-3-(naphthalen-1-yl)propenoic acid).
In other preferred compounds of formula 1a where B is (3), C is a five-membered heterocyclic ring. Examples of such compounds are (Z)-3-(6-chlorobenzo[1,3]dioxol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid,
(Z)-3-(benzothiazol-6-yl)-2-[[2-chloro-4-[[(3 hydroxybenzyl) amino]carbonyl]benzoyl]amino]propenoic acid,
(Z)-3-(2,1,3-benzoxadiazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]propenoic acid,
and (Z)-3-(2,1,3-benzothiadiazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]propenoic acid.
In yet other preferred compounds of formula 1a where B is (3), C is a heterocyclic ring with 1 to 3 nitrogens. Examples of such compounds are
(Z)-3-(1H-benzotriazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl) amino]carbonyl]-6-methylbenzoyl]amino]propenoic acid,
(Z)-3-(1H-benzotriazol -5-yl) -2-[[2-bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]propenoic acid,
(Z)-3-(1H-benzotriazol-5-yl)-2-[[2,6-dimethyl-4-[[(3-hydroxybenzyl]amino]carbonyl]benzoyl]amino]propenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(1-methyl-1H-indol-6-yl)propenoic acid
and (Z)-2-[[4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoyl]amino]-3-(1H-indol-6-yl)propenoic acid.
Also part of this invention are compounds of formula 1a where B is (4), (i.e. B is 
where X and Y are independently methylene or nitrogen). An example of such a compound is
(Z)-2-[[bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]-3-(piperidin-4-yl)propenoic acid.
In other compounds of formula 1a, B is (5) (i.e 
where at least one of T, U, V, or W is nitrogen, and any of T, U, V or W which is carbon may be substituted with lower alkyl, lower alkyl amino, lower alkoxy, hydroxy, aminosulfonyl, halogen, cyano, amino, or nitro). In preferred such compounds, the carbon is unsubstituted or substituted with lower alkoxy. Examples of such compounds are
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]-3-(pyridin-2-yl)propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2,4-dimethoxypyrimidin-5-yl) propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzy)amino]carbonyl]benzoy]]-3-(pyridin-3-yl)propenoic acid,
and (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(pyridin-4-yl)propenoic acid.
This invention includes compounds of formula 1a where B is (6) (i.e. B is 
and Y is carbon or nitrogen). Examples of such compounds are (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid, (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid,
(Z)-2-[[4-[[(3-hydroxybenzyl) amino]carbonyl]-2-methylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid,
and (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(quinolin-2-yl)propenoic acid.
Also part of this invention are compounds of formula 1a where B is (7) (i.e. B is a five-membered aromatic ring with 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur which ring may be unsubstituted or mono- or di- substituted with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, substituted amino, or which ring may be fused with a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms which heteroatoms are selected from nitrogen, oxygen, and sulfur).
In preferred compounds of formula 1a where B is (7), B is thiadiazole. An example of such a compound is (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]-3-(4-methyl-[1,2,3]thiadiazol-5-yl)propenoic acid.
In other preferred compounds of formula 1a where B is (7), B is an unsubstituted five-membered aromatic ring with 1 heteroatom selected from nitrogen, oxygen, and sulfur or with 1 to 3 nitrogen heteroatoms. Examples of such compounds are (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]-3-(thien-2-yl)propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(thien-3-yl)propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(furan-3-yl)propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(1H-imidazol-4-yl)propenoic acid, and
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(1H-[1,2,4]triazol-3-yl)propenoic acid.
In yet other preferred compounds of formula 1a where B is (7),B is a five-membered aromatic ring fused with phenyl. Examples of such compounds are
(Z)-3-(benzo[b]thiophen-3-yl)-2-[[2-bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]propenoic acid,
(Z)-3-(benzothiazol-2-yl)-2-[[2-bromo-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]propenoic acid,
and (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(1-methyl-1H-benzodiazol-2-yl)propenoic acid.
In other preferred compounds of formula 1a where B is (7), B is thiazole which is unsubstituted or is mono or di-substituted with amino, lower alkyl, trifluoromethyl, substituted amino or halogen. Examples of such compounds are
(Z)-2-[[2-bromo-4-[[(3- hydroxy-benzyl)amino]carbonyl]benzoyl]amino]-3-(thiazol-2-yl)propenoic acid,
(Z)-3-(2-aminothiazol-5-yl)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl) amino]carbonyl]benzoyl]amino]-3-(2-ethyl-4-methylthiazol-5-yl)propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-dimethylamino-thiazol-5-yl)propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-methylthiazol-4-yl)propenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-methyl-2-(1-methylethyl)thiazol-5-yl]propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(morpholin-4-yl)thiazol-5-yl]propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(piperazin-1-yl)thiazol-5-yl]propenoic acid,
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid sodium salt,
(Z)-3-(2-amino-4-trifluoromethylthiazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-chlorothiazol-5-yl)propenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-methylamino-4-trifluoromethylthiazol-5-yl)propenoic acid,
(Z)-2-[[2,6-dimethyl-4-[[(3-hydroxybenzyl]amino]carbonyl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid,
(Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(1-methylethyl)thiazol-5-yl]propenoic acid and
(Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-methyl-4-(1-methylethyl)thiazol-5-yl]propenoic acid;
(Z)-2-[[2-bromo-4-[[3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(trifluoromethyl)thiazol-2-yl]propenoic acid; and
(Z)-2-[[2-bromo-4-[[3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(1-methylethyl)thiazol-2-yl]propenoic acid.
This invention is directed to compounds of formula 1 having the formula 
where R4 and R5 are hydrogen, methyl, ethyl or halogen, except that R4 and R5 cannot both be hydrogen, and B is selected from options (1), (2), (3), (4), (5), (6), and (7). It is preferred that R4 be halogen and R5 be hydrogen.
In some compounds of formula 1b (especially where R4 is halogen and R5 is hydrogen), B is (7) (i.e. B is a five-membered aromatic ring with 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur which ring may be unsubstituted or mono- or di-substituted with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, substituted amino, or which ring may be fused with a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms which heteroatoms are selected from nitrogen, oxygen, and sulfur).
In preferred compounds of formula 1b where B is (7) (especially where R4 is halogen and R5 is hydrogen), B is thiazole. An example of such a compound rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid.
In other preferred compounds of formula 1b (especially where R4 is halogen and R5 is hydrogen), B is (6) (i.e. B is 
and Y is carbon or nitrogen). An example of such a compound is rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid.
This invention is also directed to compounds of formula 1 having the formula 
where R4 and R5 are hydrogen, methyl, ethyl or halogen but not both hydrogen; and B is selected from options (1), (2), (3), (4), (5), (6), and (7). In preferred compounds R4 is halogen and R5 is hydrogen.
In compounds of formula 1c (especially where R4 is halogen and R5 is hydrogen), B is (7) (i.e. B is a five-membered aromatic ring with 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur which ring may be unsubstituted or mono- or di- substituted with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, substituted amino, or which ring may be fused with a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms which heteroatoms are selected from nitrogen, oxygen, and sulfur). In preferred such compounds, B is thiazole. An example of such a compound is rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-dimethylthiazol-5-yl)propenoic acid.
In other compounds of formula 1c (especially where R4 is halogen and R5 is hydrogen), B is (6) (i.e. B is 
wherein Y is carbon or nitrogen). An example of such a compound is rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid.
This invention includes compounds of formula 1 having the formula 
where R4 and R5 are hydrogen, methyl, ethyl or halogen, but not both hydrogen; and B is selected from options (1), (2), (3), (4), (5), (6), and (7). In preferred compounds, R4 is halogen and R5 is hydrogen. In preferred such compounds B is (7), (i.e. where B is a five-membered aromatic ring with 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur which ring may be unsubstituted or mono- or di- substituted with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, substituted amino, or which ring may be fused with a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms which heteroatoms are selected from nitrogen, oxygen, and sulfur), especially where R4 is halogen and R5 is hydrogen. An example of such a compound is (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid.
In other preferred compounds of formula 1d (especially where R4 is halogen and R5 is hydrogen), B is (6) (i.e. B is 
wherein Y is carbon or nitrogen). An example of such a compound is (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid.
This invention is also directed to compounds of formula 1 having formula 
where R4 and R5 are hydrogen, methyl, ethyl or halogen but not both hydrogen, and B is selected from options (1), (2), (3), (4), (5), (6), and (7). In preferred such compounds, R4 is hydrogen and R5 is halogen.
In preferred compounds of formula 1e (especially where R4 is halogen and R5 is hydrogen), B is (6) (i.e. B is 
wherein Y is carbon or nitrogen). An example is (Z)-2-[[4-[[(3-aminobenzyl)amino]carbonyl]-2-bromobenzoyl]amino]-3-(quinolin-3-yl)propenoic acid.
In preferred compounds of formula 1e (especially where R4 is halogen and R5 is hydrogen), B is (7) (i.e. B is a five-membered aromatic ring with 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur which ring may be unsubstituted or mono- or di- substituted with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, substituted amino, or which ring may be fused with a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms which heteroatoms are selected from nitrogen, oxygen, and sulfur). An example of such a compound is (Z)-2-[[4-[[(3-aminobenzyl)amino]carbonyl]-2-bromobenzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid.
This invention is also directed to compounds of formula 1 having the formula 
where R4 and R5 are hydrogen, methyl, ethyl or halogen but not both hydrogen; and B is selected from options (1), (2), (3), (4), (5), (6), and (7). In preferred such compounds, R4 and RW are methyl. It is also preferred that B is (7) (i.e. B is a five-membered aromatic ring with 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur which ring may be unsubstituted or mono- or di-substituted with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, substituted amino, or which ring may be fused with a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms which heteroatoms are selected from nitrogen, oxygen, and sulfur). Examples of such compounds are (Z)-2-[[4-[[(3,5-difluorobenzyl)amino]carbonyl]-2,6-dimethylbenzoyl]amino]-3-(4-methyl-1H-imidazol-5-yl)propenoic acid, and (Z)-2-[[4-[[(3,5-difluorobenzyl)amino]carbonyl]-2,6-dimethylbenzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid.
Also preferred are compounds of formula 1f where B is (6) (i.e. B is 
and Y is carbon or nitrogen), especially where R4 and R5 are methyl. An example of such a compound is (Z)-2-[[4-[[(3,5-difluorobenzyl]amino]carbonyl]-2,6-dimethylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid.
This invention is directed to compounds of formula 1-1 having the formula 
where R4 and R5 are hydrogen, methyl, ethyl or halogen, but not both hydrogen; and B is selected from options (1), (2), (3), (4), (5), (6), and (7), preferably (7). In preferred such compounds B is a five-membered aromatic ring with 1 to 2 heteroatoms selected from nitrogen and sulfur, which ring may be unsubstituted, or mono- or di- substituted with lower alkyl, cycloalkyl, trifluoroloweralkyl, amino, halogen, or substituted amino, especially where B may be unsubstituted or disubstituted with lower alkyl. Examples of such compounds are (Z)-2-[[2-bromo-4-[[[(1H-indol-4-yl) methyl]amino]carbonyl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid and (Z)-2-[[2-chloro-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(thien-2-yl)propenoic acid.
Also preferred are compounds of formula 1-1a where B is (3) (i.e. 
where R10 is hydrogen, hydroxy, halogen, or lower alkyl and C is a five- or six-membered ring with 0 to 3 heteroatoms, which heteroatoms are selected from nitrogen, oxygen, and sulfur, which ring may be unsubstituted or mono- or di- substituted with lower alkyl, cycloalkyl, or substituted amino). Examples of such compounds are (Z)-3-(3H-benzotriazol-5-yl)-2-[[2-bromo-4-[[[(1H-indol-4-yl)methyllamino]carbonyl]benzoyl]amino]propenoic acid,
(Z)-3-(benzothiazol-6-yl)-2-[[2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]amino]propenoic acid, and
(Z)-2-[[2-chloro-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(naphthalen-2-yl)propenoic acid.
Also preferred are compounds of formula 1-1a where B is (2) (i.e. B is 
where R6 R7 R8 and R9 are independently hydrogen, hydroxy, aminosulfonyl, halogen, lower alkoxy, cyano, amino, or nitro). Examples are (Z)-2-[[2-chloro-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]amino]-3-phenylpropenoic acid and (Z)-2-[[2-chloro-4-[[[(1H-indol-4-yl)methyl]aminol]carbonyl]benzoyl]amino]-3-(2-hydroxyphenyl)propenoic acid.
In other preferred compounds of formula 1-1a, B is (6) (i.e. B is 
and Y is carbon or nitrogen). An example of such a compound is (Z)-2-[[2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid. Related compounds of this invention are (Z)-2-[[2-bromo-4-[[[(1H-indol-6-yl)methylano]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid, and (Z)-2-[[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]amino]3-(quinolin-3-yl)propenoic acid.
In other preferred compounds of formula 1-1a, B is (5) (i.e. 
where at least one of T, U, V, or W is nitrogen, and any of T, U, V, or W which are carbon may be substituted with lower alkyl, lower alkyl amino, lower alkoxy, hydroxy, aminosulfonyl, halogen, cyano, amino, or nitro). An example of such a compound is (Z)-2-[[2-chloro-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(pyridin-2-yl)propenoic acid.
Also part of this invention are compounds of formula 1-1 having the formula 
where R4 and R5 are hydrogen, methyl, ethyl or halogen, but not both hydrogen; and B is selected from options (1), (2), (3), (4), (5), (6), and (7).
Compounds of formula 1-1b include compounds where B is (2), especially where B is 
R6, R7, R8, and R9 are hydrogen. An example is [Z, (R)]-2-[2,6-dimethyl-4-[[[1-naphthalen-1-yl)ethyl]amino]carbonyl]benzoyl]amino]-3-phenylpropenoic acid.
In other compounds of formula 1-1b, B is (3), especially where B is 
and R10 is hydrogen and C is triazole. Examples of such compounds are [Z, (R)]-3-(1H-benzotriazol-5-yl)-2-[[2,6-dimethyl-4-[[[1-naphthalen-1-yl)ethyl]amino]carbonyl]benzoyl]amino]propenoic acid and [Z, (R)]-3-(1H-benzotriazol-5-yl)-2-[[2,6-dichloro-4-[[[l-naphthalen-1-yl)ethyl]amino]carbonyl]benzoyl]amino]propenoic acid.
In other compounds of formula 1-1b, B is 
An example of such a compound is [Z,(R)]-2-[[2,6-dimethyl-4-[[[(1-(naphthalen-1-yl)ethyl]amino]carbonyl]benzoyl]amino]-3-(pyridin-4-yl)propenoic acid.
Preferred compounds of formula 1-1b include compounds where B is (7), especially where B is a five-membered aromatic ring with one to two heteroatoms selected from N and S which ring may be mono or di substituted with lower alkyl. Examples are [Z, (R)]-2-[[2,6-dimethyl-4-[[[1-naphthalen-1-yl)ethyl]amino]carbonyl]benzoyl]amino]-3-(4-methyl-1H-imidazol-5-yl)propenoic acid,
[Z, (R)]-2-[[2-chloro-4-[[[1-naphthalen-1-yl) ethyl]amino]carbonyl]benzoyl]amino]-3-(thien-2-yl)propenoic acid,
[Z, (R)]-2-[[2,6-dimethyl-4-[[[1-naphthalen-1-yl)ethyl]amino]carbonyl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid
and [Z, (R)]-2-[[2,6-dimethyl-4-[[[1-naphthalen-1-yl) ethyl]amino]carbonyl]benzoyl]amino]-3-(1H-imidazol-2-yl)propenoic acid.
Formula 1-1b includes compounds where B is (6). Examples of such compounds are [Z,(R)]-2-[[2,6-dichloro-4-[[[(1-(naphthalen-4-yl)ethyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid and [Z, (R)]-2-[[2,6-dimethyl-4-[[[(1-naphthalen-1 yl)ethyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid.
This invention is also directed to compounds of formula 1, which compounds have the formula 
where R1 is hydrogen, hydroxy, amino or halogen, R2 is hydrogen, hydroxy, or halogen and R3 is hydrogen; R4 and R5 are hydrogen, methyl, ethyl, or halogen but not both hydrogen, and B is selected from options (1), (2), (3), (4), (5), (6), and (7).
This invention is also directed to compounds of formula 1-1 having the formula 
where R1 is hydrogen and R2 and R3 taken together with the ethenylene group connecting them form phenyl, pyrrole, pyrroline, oxopyrroline, pyrazole, triazole, or imidazole; R4 and R5 are hydrogen, methyl, ethyl, or halogen but not both hydrogen, and B is selected from options (1), (2), (3), (4), (5), (6), and (7).
Also part of this invention are prodrug compounds (and their pharmaceutically acceptable salts). Any compound of this invention is also contemplated in prodrug form. By prodrug is meant a metabolic precursor of a drug which when administered to a patient breaks down into the drug and acceptable by-products. In the prodrugs of this invention, the carboxy group found in the formulae above is replaced by other groups, which groups come off when administered to the patient, leaving a hydrogen and reconstituting the carboxy group. Any individual compound of this invention may be iobtained as a prodrug described below.
Prodrugs of this invention include a compound of formula 
wherein R2 and R3 taken together with the ethenylene group connecting them form phenyl, pyrrole, pyrroline, oxopyrroline, pyrazole, triazole, or imidazole; R4 and R5 are hydrogen, methyl, ethyl, or halogen but not both hydrogen, and R6 is one of the following groups: 
where R7 is lower alkyl, xe2x80x94(CH2)rxe2x80x94N(CH3)2, 
Z is oxygen or NH, R8 is hydrogen or methyl and R9 is lower alkyl or cycloalkyl and m, n, and r are 1 to 5 (each of m, n, and r is preferably 2).
A is one of the following groups: 
B is selected from options (1), (2), (3), (4), (5), (6), and (7). When R6 is 
xe2x80x83it is preferred that R7 is unbranched lower alkyl, especially ethyl. It is also preferred that n is 2, especially when R6 is xe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)rxe2x80x94N(CH2)2, 
It is also preferred that R6 is 
especially when R8 is hydrogen or methyl and R9 is ethyl or cyclohexyl. In a preferred compound, R6 is 
and n is 2.
Another prodrug of this invention is a compound of formula 
wherein R1 is hydrogen, hydroxy, amino or halogen, R2 is hydrogen, hydroxy or halogen and R3 is hydrogen, R4 and R5 are hydrogen, methyl, ethyl, or halogen but not both hydrogen, and R6xe2x80x2 is one of the following groups 
where R7 is lower alkyl xe2x80x94(CH2)rxe2x80x94N(CH3)2, 
Z is oxygen or NH, R8 is hydrogen or methyl and R9 is lower alkyl or cycloalkyl and m, n, and r are 1 to 5 (each of m, n, and r is preferably 2). A is one of the following groups: 
B is selected from options (1), (2), (3), (4), (5), (6), and (7). When R6 is 
it is preferred that R7 is unbranched lower alkyl, especially ethyl. It is also preferred that n is 2, especially when R6 is xe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)rxe2x80x94N(CH3)2, 
or 
It is also preferred that R6 is 
especially when R8 is hydrogen or methyl and R9xe2x80x2 is ethyl or cyclohexyl. In a preferred compound, R6 is 
and n is 2. An example of such a compound is (Z)-2-[[2-bromo-4-[[(3-hydroxy-benzyl]amino]carbonyl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid 2-(morpholin-4-yl)ethyl ester.
Other prodrugs of this invention can be obtained from any compound of this invention by known modifications at the R. or R2 position of formula 1 or formula 1-1 using known methods.
By halogen in general is meant bromine, chlorine, fluorine and iodine. For any compound of this invention, the preferred halogens are bromine, chlorine, and fluorine.
By lower alkyl is meant saturated hydrocarbon chains such as methyl, ethyl, propyl. butyl and the like. The length of the chains is preferably from 1 to 10 carbons, more preferably from 1 to 4 carbons, inclusive of any branching carbons as defmed in this paragraph. A lower alkyl group of this invention may be branched, which means a lower alkyl group that contains a carbon which is bonded to at least three other carbons, such as isopropyl or 2-ethyl-4-methylpentyl. A lower alkyl substituent may also be unbranched, which means that it does not contain any carbons bonded to more than two other carbons. Examples of various lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl. Preferred lower alkyl groups are methyl, ethyl, propyl (n or iso), and butyl (n, iso, sec, or tert). Lower alkyl groups may be substituted with another group, preferably halogen, such as fluorine. Such substitution may be in one or more positions. A preferred such group is trifluoroalkyl, where three of the carbons of the lower alkyl group are substituted with fluorine. A particularly preferred group is trifluoromethyl.
By cycloalkyl is meant a saturated hydrocarbon ring which is from 3 to 10 carbons in size, preferably 3 to 6 carbons, most preferably 5 or 6 carbons.
By lower alkoxy is meant a lower alkyl as defined above which may be branched or unbranched as also defmed above and which is bonded by an oxygen to another group (i.e. alkyl ethers). Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. Methoxy is preferred.
By substituted amino is meant an amino group which is mono- or di-substituted with another group, preferably a lower alkyl (e.g., methyl) or a lower acyl group (e.g., acetyl). Examples of such groups include piperazinyl, morpholino, and lower alkylamino. By lower alkylamino is meant an amino group which is substituted by one or more lower alkyl group. Examples are methylamino, ethylamino, dimethylamino, and the like. Preferred are piperazinyl, morpholino, and dimethylamino, especially piperazinyl and morpholino.
Rings of this invention may include one or more heteroatoms (e.g. heterocycles). The heteroatoms are nitrogen, oxygen, and sulfur. Unless otherwise specified, any such ring may include one, two, or three heteroatoms in any chemically acceptable combination, such as pyrroline, oxazole, dioxolane, triazine, dithiazole, pyridine, dithiane, thiomorpholine, and the like. Substituted rings of this invention are generally understood to be substituted only on those atoms which are chemically able to accept substituents. For example, substitution would not occur on the N of a pyridine or at a position of fusion between two aromatic rings. Multiple substitution means substitution with multiple substituents (which may be the same or different) at the same number of positions, i.e. with no more than one substituent per position. For example, xe2x80x9cdisubstitutedxe2x80x9d means substitution with two substituents at two different positions, one substituent per position.
Taking R2 and R3 together with the ethenylene group connecting them to form phenyl, pyrroline, pyrrole, oxopyrroline, pyrazole, triazole, or imidazole means that the group formed by R2 and R3, and the ethenylene group connecting them, when fused with the phenyl of formula 1 to which R2 and R3 are attached, results in a bicyclic ring. Accordingly, when R2 and R3, and the ethenylene group, form phenyl, the bicyclic ring resulting from fusion with the phenyl of formula 1 is naphthyl. With regard to the remaining bicyclic rings, it is preferred that the point of attachment be at the 4-position of the heterocyclic ring system. Accordingly, R2 and R3 and the ethenylene group form triazole to provide benzotriazole on fusion with the phenyl, and form imidazole to provide benzimidazole, on fusion with phenyl. R2 and R3 and the ethenylene group form pyrroline, to provide indoline on infusion with the phenyl. R2 and R3 and the ethenylene group form pyrazole, to provide indazole on fusion with the phenyl. R2 and R3 form oxopyrroline to provide oxindole on fusion with the phenyl. R2 and R3 and the ethenylene group form pyrrole to provide indole on fusion with the phenyl.
A five- or six-membered ring with 0 to 3 heteroatoms is understood to include aromatic and nonaromatic rings. Examples of five-membered rings with 0 heteroatoms are cyclopentyl or cyclopentadienyl, while examples of six-membered rings with 0 heteroatoms are cyclohexyl or phenyl. Preferred rings are phenyl, triazole, thiazole, imidazole, dioxolane, and oxadiazole. The ring may be unsubstituted, or substituted with one or more groups. Preferred substituents are lower alkyl, cycloalkyl, amino, and substituted amino. Lower alkyl is especially preferred.
With regard to the ring of this invention where at least one of positions T, U, V, or W is nitrogen, and any of positions T, U, V or W which is carbon may be substituted with hydroxy, aminosulfonyl, halogen, lower alkoxy, cyano, amino, or nitro, the preferred ring substituent is lower alkoxy. Preferably either T, U, V, or W are nitrogen. Any two or more of these positions may also be nitrogen, for example T and V, or U and V and W, or U and V, etc. In any of these rings, the positions which are not nitrogen are carbon. Thus in a ring where W is nitrogen and positions T, U, and V are not specified, positions T, U, and V are carbon. The rings may be substituted as described only at carbon positions.
The five-membered aromatic ring of this invention has one to three heteroatoms selected from nitrogen, oxygen, and sulfur. This ring may be unsubstituted or mono- or di- substituted as described above at any chemically acceptable position(s). Preferred substituents are lower alkyl, trifluoroloweralkyl, amino, halogen, substituted amino. This ring may also be fused with a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. The ring may also be fused with phenyl preferably at positions not adjacent to the attachment point. Preferred rings are thiazole and triazole. By attachment point is meant the position on the ring where it is attached to the remainder of the molecule. Positions adjacent to the attachment point are the positions flanking the attachment point, one going clockwise and the other going counterclockwise from the attachment point. The preferred position for a ring heteroatom is two positions from the attachment point.
R4 and R5 are symmetric in that they occupy equivalent positions. Therefore for purposes of this application, a compound where R4is a first substituent while R5 is a second substituent, is effectively equivalent to the compound where R5is identified as the first substituent and R4is identified as the second substituent (all other groups being identical). For example a compound where R4is chlorine and R5 is methyl is equivalent to a compound where R5 is chlorine and R4is methyl. Therefore description of one such compound also describes its equivalent. This does not mean in general that R4 and R5 must be the same. In any compound of this invention, R4 and R5 are independent of each other and accordingly may be the same or different. Thus in the context of this application, the phrase xe2x80x9cR4 is chlorine or bromine and R5 is hydrogenxe2x80x9d describes a compound which is equivalent to the compound described by the phrase xe2x80x9cone of R4 or R5 is chlorine or bromine and the other is hydrogen.xe2x80x9d (all other groups being identical).
Pharmaceutically acceptable salts of all the compounds of this invention are included. Pharmaceutically acceptable salts and esters are well known in the art and can be made by conventional methods taking into account the chemical nature of the compound. Examples of pharmaceutically acceptable salts for acidic compounds are alkali metal or alkaline earth metals such as sodium, potassium, calcium, magnesium, basic amines or basic amino acids, ammonium or alkyl ammonium salts. Particularly desirable salts for compounds of this invention are sodium salts. The sodium salt of any compound of this invention is easily obtained from the acid by treatment with sodium hydroxide. For basic compounds, examples are salts of inorganic or organic acids such as hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, citric, formic, fumaric, maleic, acetic, succinic, tartaric, methanesulfonic, and p-toluenesulfonic. Examples of pharmaceutically acceptable esters include unbranched lower alkyl esters such as methyl, ethyl, n-propyl and the like.
The compounds of this invention and their pharmaceutically acceptable salts inhibit the binding of LFA-1, expressed on activated lymphocytes, and monocytes, to the immunoglobulin ICAM-1 which is expressed on activated endothelial cells, epithelial cells, synovial cells, myocytes, glial cells and neurons as well as on lymphocytes and antigen presenting cells. The compounds in this invention can therefore be used in the treatment of disorders that involve the binding of LFA-1 with ICAM-1. This pharmaceutical activity demonstrates the utility of the compounds of this invention. Specifically, the compounds of the invention are preferably used in the treatment of psoriasis. In vitro assays for determining the desired pharmaceutical activity are provided below in the Examples. An indicator of pharmaceutical activity is the ability to inhibit a biological activity associated with LFA-1, such as T lymphocyte proliferation in a mixed lymphocyte reaction. Competitive binding assays, known in the art also indicate pharmaceutical activity. In vivo assays for pharmaceutical activity are also provided. Compounds of this invention inhibit induced paw and ear swelling in mice. Activities within the ranges exemplified in the Examples are indicative of desired pharmaceutical activity.
Accordingly part of this invention are pharmaceutical compositions which comprise compounds of this invention, for example compounds of formulae 1, 1a-1g, 1-1, 1-1a-1-1-1c, 2, and 2-1, and a pharmaceutically acceptable carrier. Compositions which include particularly preferred individual compounds of this invention, are also particularly preferred.
For example, especially preferred compositions contain compounds of formula 1 described above where R1 is hydroxy or amino and R2 and R3 are hydrogen and compounds of formula 1-1 where R2 and R3 together with the ethenylene to which they are attached form phenyl, pyrazole or pyrrole. In these compounds, A is 
R4 and R5 are lower alkyl or halogen; and B is 
where R11 is hydrogen, lower alkyl, substituted amino, or amino and R12 is hydrogen, trifluoroloweralkyl, or lower alkyl in addition to other active or inactive ingredients as described below.
The pharmaceutical compositions can be made up in any conventional form, including a solid form for oral administration such as tablets, capsules, pills, powders, granules, and the like. The pharmaceutical compositions may be sterilized and/or may contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure, and/or buffers. Another active compound may be added.
Typical preparations for administration by injection would be sterile aqueous solutions of the compounds of this invention including water/buffered solutions. Injection is by any conventional mode, e.g. intravenous, intramuscular, subcutaneous, or intraperitoneal. Pharmaceutically acceptable carriers or vehicles may include fluid such as water, nutrient and electrolyte replenishers, sugars such as sucrose, glucose, invert sugar. Preservatives and other additives may also be present such as antibiotics and antioxidants. Adjuvants which may be present include alcohol, polyols, glycerol, vegetable oil. Pharmaceutically acceptable excipients typically used in such preparations may be added to control such properties as pH, viscosity, sterility, stability, and dissolution rate.
Typical preparations for oral administration contain compounds of this invention in association with a compatible pharmaceutically acceptable carrier material. Any conventional pharmaceutically acceptable carrier material can be utilized. Any conventional oral dosage form such as tablets, capsules, pills, powders, granules, and the like may be used. The pharmaceutically acceptable carrier can be an organic or inorganic inert carrier material suitable for oral administration. Suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene-glycols, petroleum jelly, water, vegetable oils, fats, liquid and semisolid polyols and the like. Furthermore, the pharmaceutical composition may contain other pharmaceutically active agents. Additional additives such as flavoring agents, preservatives, stabilizers, antioxidants, emulsifying agents, masking agents, buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding. Administration by suppository is also possible. Carriers for this purpose include oils, waxes, fats, polyols.
Also part of this invention is a method of treating psoriasis which comprises administering an amount of a any compound of this invention effective to reduce or eliminate the symptoms of psoriasis in a patient affected by the disease. Preferred for use in the method are those preferred compositions described in the paragraphs immmediately above.
The compounds of the invention can be administered orally, rectally, or parentally, e.g., intravenously, intramuscularly, by infusion, subcutaneously, intrathecally or transdermally; or sublingually, or as opthalmalogical preparations, or as an aerosol for the treatment of pulmonary inflammation. Capsules, tablets, suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, salves or spray solutions are examples of administration forms.
The compounds of the invention are preferably administered orally. The dosages in which the compounds of the invention are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of administration. The dosage for any given person may be determined by a skilled person based on the information provided here. Dosages may be determined by any conventional means, however in the methods of this invention, it is preferred that the amount of compound is from about 50 mg to 2 grams administered twice daily. The compound may be administered by a skilled person to create a preselected circulatory concentration.
The compounds of this invention can be prepared by a skilled practitioner with the Synthesis provided below. The Examples which follow are illustrative and are not intended to limit the invention in any way. 
A compound of struture 13 (R6=R7=methyl) is commercially available. 
The starting materials of structure 14 are generally known compound. 
The starting materials of structure 21, 25, 26 are generally known compounds. 
The starting materials of structure 30, 31, 32 and 23 are generally known compounds. 
Some compounds of structure 34 are known. Others can be prepared according to the following Scheme: 
The compounds of the present invention can be prepared by any conventional means. For example, compounds of structure 1 can be manufactured by
(a) for the preparation of a compound of structure 1 in which R6 is hydrogen from a compound of structure 2 in which R6 is an optionally substituted alkyl group that can be cleaved under acidic conditions, such as tert-butyl or aralkyl (for example Wang resin) and the like, by treatment with a strong acid, or
(b) for the preparation of a compound of structure 1 in which R6 is hydrogen from a compound of structure 2 in which R6 is a lower alkyl or aralkyl group, unbranched on the carbon next to oxygen, for example, the methyl, ethyl, n-propyl, n-butyl, benzyl groups, and the like, by treatment with alkali metal hydroxide solution, or
(c) if desired, separating a mixture of diastereomers into the optically pure diastereomers, and/or
(d) if desired, converting a compound of structure 1 which bears a basic nitrogen into a pharmaceutically acceptable acid addition salt, and/or
(e) if desired, converting a compound of structure 1 in which R6 is hydrogen into a pharmaceutically acceptable alkali metal salt or
(f) for the preparation of compounds of structure 1 where R6 represents lower alkyl, dialkylaminolower alkyl, (4-morphilino)lower alkyl, (1-piperadino)lower alkyl, (1-pyrrolidino)lower alkyl and the like by esterification of a compound of structure 1 where R6 is hydrogen.
The cleavage of an acid-labile ester moiety in accordance with procedure (a) can be carried out in accordance with methods that are known per se. For example, the ester may be treated with a strong inorganic acid, for example a hydrohalic acid such as hydrogen chloride or hydrogen bromide, or a strong organic acid, for example a halogenated alkane carboxylic acid such as trifluoroacetic acid and the like. The reaction is conveniently carried out in the presence of an inert organic solvent (such as dichloromethane) and at a temperature between about zero degrees and about room temperature, preferably at about room temperature.
The cleavage of an alkali-labile ester moiety in accordance with procedure (b) can be carried out according to known procedures. For example, the ester may be treated with an alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable inert solvent system, for example a mixture of methanol and water or a mixture of methanol, tetrahydrofuran and water. The reaction is carried out at a temperature between about zero degrees and about 60 degrees, preferably between room temperature and about 50 degrees.
The optional separation in accordance with procedure (c) can be carried out according to known methods such as fractional crystallization, column chromatography, thin-layer chromatography, high pressure liquid chromatography etc.
The optional conversion of a compound of structure 1 into a pharmaceutically acceptable acid addition salt in accordance with procedure (d) can be effected by conventional means. For example, the compound can be treated with an inorganic acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., or with an appropriate organic acid such as acetic acid, trifluoroacetic acid, citric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, or the like. The optional conversion of a compound of structure 1 into a pharmaceutically acceptable alkali metal salt in accordance with procedure (e) can be effected by conventional means. For example, the compound can be treated with an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like. The esterification of compounds of structure 1 where R6 represents hydrogen or the alkali metal salt prepared by procedure (e) can be effected by a variety of different methods, such as those conventionally used to prepare esters of carboxylic acids. In accordance with method (f) the sodium salt of structure 1 is reacted with an alcohol in the presence of a condensing agent. For example, the compounds of structure 1, in which R6 represents 2-(4-morphilino)ethyl, can be prepared by treatment of the sodium salt of compounds of structure 1 with 2-(4-morphilino)ethanol in the presence of an 1,3-disubstitutedcarbodiimide, for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction is conveniently carried out in an inert solvent, for example tetrahydrofuran optionally in the presence of a catalyst, N,N-dimethylaminopyridine, at a temperature between about room temperature and about 40 degrees, preferably at about room temperature. 
The compounds of structure 2 in which R6 represents an optionally substituted alkyl moiety can be prepared by means which are well known to one of ordinary skill in the field. For example, they can be prepared by the reaction of compounds of structure 3, in which R7 represents an optionally substituted alkyl moiety, with compounds of structure 4 in accordance with procedure (g) by using the Horner-Emmons modification of the Wittig reaction well known to one of ordinary skill in the art. For example, the transformation can be carried out by reaction of the phosphonate ester of structure 3 with a deprotonating agent, preferably 1,1,3,3-tetramethylguanidine in an inert solvent, for example, tetrahydrofuran, at a temperature of from xe2x88x9245 degrees to about room temperature, preferably at xe2x88x9245 degrees to xe2x88x9220 degrees. Within a short period, usually about 5 minutes, the aldehyde of structure 4 is added and the reaction is then maintained at a temperature of from xe2x88x9245 degrees to about room temperature. 
The coupling of compounds 5 with compounds of structure 6 can be carried out in accordance with procedure (h) using methods well known to one of ordinary skill in the art. For example, the transformation can be carried out by reaction of carboxylic acids of structure 5 with an amine of structure 6 in the presence, if necessary, of a coupling agent, many examples of which are well known per se in peptide chemistry. The reaction is conveniently carried out by treating the carboxylic acid of structure 5 with the amine of structure 6 in the presence a coupling agent such as O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and in the optional additional presence of a substance that increases the rate of the reaction, such as 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole, in an inert solvent, such as a chlorinated hydrocarbon (e.g., dichloromethane) or N,N-dimethylformamide or N-methylpyrrolidinone, at a temperature between about zero degrees and about room temperature, preferably at about room temperature. Alternatively, activation of the carboxylic acid of structure 5 can be achieved by pretreatment of the acid with triphenylphosphine and N-chlorosuccinimide in an inert solvent, such as a chlorinated hydrocarbon (e.g., dichloromethane) at a temperature between about zero degrees and about room temperature, preferably at about zero degrees, and the formed intermediate is then allowed to couple with the amine of structure 6.
Compounds of structure 4 are generally known compounds, or if they are not known compounds, they can be prepared by methods that are well known in the field of organic chemistry. For example, they can be prepared by
(i) oxidation of compounds of structure 8.
(j) formylation of a compound of structure 10, where B represents represents a suitably reactive aromatic or heteroaromatic species, with a masked formylating reagent under Friedel-Crafts conditions.
(k) reaction of a formamide with a metalated species, B-M, derived from a compound of structure 10, where B is an aryl or heteroaromatic group and M is lithium or sodium.
The oxidation of compounds of structure 8 in accordance with procedure (i) can be effected by any conventional means with the proviso that any other oxidizable functionality present in the group B is shielded by using an appropriate protecting group. The reaction may be carried out by treating a compound of structure 8 with a suitable oxidizing agent, of which among others are manganese dioxide, o-iodoxybenzene and sulfur trioxide-pyridine complex. For example, a compound of structure 8 is treated with manganese dioxide in an inert solvent, such as a chlorinated hydrocarbon (e.g., dichloromethane) or acetonitrile, at a temperature of between about zero degrees and about room temperature, preferably at about room temperature. For the alkylation of compounds of structure 10 with a masked formylating agent, in accordance with procedure (j) a variety of procedures can be used. For example a compound of structure 10, where B represents a suitably reactive aromatic or heteroaromatic species, is treated with dichloromethyl n-butyl ether in the presence of a Lewis acid, preferably titanium tetrachloride. The reaction is conveniently carried out in an inert solvent such as carbon disulfide at a temperature between about zero degrees and about room temperature, preferably at about room temperature.
The conversion of compounds of structure 10 into compounds of structure 8 in accordance with procedure (k) may be carried out by methods known per se. For example, the reaction may be conveniently carried out by treating a compound of structure 10, where B is an aryl or heteroaromatic group, with an alkyl lithium, for example n-butyl lithium, at a temperature of from zero degrees to about xe2x88x9278 degrees, preferably at about xe2x88x9278 degrees in an inert solvent such as tetrahydrofuran to form the aryl lithium or heteroaryl lithium. The metalated species is then reacted in situ with a N,N-disubstitutedformamide, e.g., N,N-dimethylformamide and the reaction is allowed to proceed at a temperature at a temperature of from room temperature to about xe2x88x9278 degrees, preferably at about room temperature.
The compounds of structure 5 are prepared by methods that are well known in the field of organic chemistry. For example, they can be prepared by:
(l) by the removal of carboxylic acid protective groups from compounds of structure 11, in which R10 represents for example an unbranched lower alkyl group (e.g., methyl or ethyl), an aralkyl group, or a tert-butyl group or the like.
(m) by carboxylation of compounds of structure 12, where R11 represents a group that can be carboxylated under noble metal catalysis, and where the rest of the molecule is stable to such treatment.
For the deprotection of ester protective groups in accordance with procedure (l), any conventional means can be used. For example, in the case where R10 represents an unbranched lower alkyl group (e.g., methyl), the reaction may be carried out by treating the compound of structure 11 with an alkali methyl hydroxide, such as potassium hydroxide, sodium hydroxide or lithium hydroxide, preferably lithium hydroxide, in an appropriate solvent, such as a mixture of tetrahydrofuran, methanol and water. The reaction is conveniently carried out at a temperature between about zero degrees and about room temperature, preferably at about room temperature.
For the carboxylation of compounds of structure 12 where R11 represents a group that can be carboxylated under noble metal catalysis, such as iodide, bromide, or trifluoromethanesulfonate, in accordance with procedure (m), a variety of procedures can be used. For example, the reaction can be carried out by reacting the compound of structure 12 with water under carbon monoxide gas at a pressure between about 14 pounds per square inch and about 50 pounds per square inch, preferably at about 40 pounds per square inch, in the presence of a noble metal catalyst such as tetrakis(triphenylphosphine)palladium(0), allylpalladium(II) chloride dimer, or dichlorobis(triphenylphosphine)palladium(II), and a base, for example a tertiary amine, such as triethylamine, in an inert solvent, such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, or the like. The reaction can be carried out at a temperature between about 40 degrees and about 100 degrees, preferably at about 80 degrees.
Compounds of structure 12, where R11 represents hydroxy, acetoxy, bromo, iodo or trifluoromethanesulfonyloxy can be made by methods similar to those outlined below in the procedures (s), (t), (u), (v) and (w) for the preparation of compounds of structure 11.
The compounds of structure 6, in which R7 represents an lower alkyl group, can prepared by the removal of amine protective groups from compounds of structure 7, in which PG represents for example an aralkoxycarbonyl group (e.g., benzyloxycarbonyl) or the like in accordance with procedure (n). The reaction may be carried out by hydrogenation in the presence of a noble metal catalyst such as palladium-on-carbon in the presence of an inert solvent (for example, an alcohol such as methanol) at about room temperature and at a pressure between about 14 pounds per square inch and about 50 pounds per square inch, preferably about 50 pounds per square inch of hydrogen.
Compounds of structure 8 are generally known compounds, or if they are not known compounds, they can be prepared by methods that are well known to one of ordinary skill in the field. The esters of structure 9, in which R8 represents an optionally branched alkyl group, may be transformed into compounds of structure 8 in accordance with procedure (o) by using a variety of reducing agents, among which are but not limited to, lithium aluminum hydride, diisobutylaluminum hydride and sodium borohydride. For example, the reaction is conducted by reacting a compound of structure 9 with diisobutylaluminum hydride in an inert solvent such as an ether (e.g., tetrahydrofuran, diethyl ether) or an aromatic hydrocarbon (e.g., toluene) at a initial temperature of from xe2x88x9278 degrees to xe2x88x9250 degrees, preferably at about xe2x88x9278 degrees. The reaction is allowed to proceed at a temperature of from about xe2x88x9278 degrees to about room temperature, preferably between zero degrees and about room temperature.
Compounds of structure 9, in which R8 represents for example an unbranched lower alkyl group (e.g., methyl or ethyl) are generally known compounds, or if they are not known compounds, they can be prepared by methods that are well known in the field. For example they can be prepared by
(p) esterification of a compound of structure 14 or
(q) for the preparation of a compound where B represents a thiazol-2-yl group by reacting a compound of structure 16 with a compound of structure 17 or
(r) for the preparation of a compound where B represents a thiazol-5-yl moiety by reacting a compound of structure 19 with a compound of structure 20.
The esterification of compounds of structure 14 can be accomplished by a variety of a different reactions, such as those conventionally used to prepare esters of carboxylic acids. In accordance with method (p) the acid of structure 14 is reacted with an lower unbranched alcohol in the presence of a condensing agent. For example, the compounds of structure 9, in which R8 represents methyl, can be prepared by treatment of compounds of structure 14 with methanol containing an 1,3-disubstituted carbodiimide, for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction is conveniently carried out in an inert solvent, for example dichloromethane optionally in the presence of a catalyst, N,N-dimethylaminopyridine, at a temperature between about room temperature and about 40 degrees, preferably at about room temperature.
The condensation of thiooxamate of structure 17, in which R9 represents for example an unbranched lower alkyl group, with an halomethylketone of structure 16, where X represents bromo or chloro and R12 is optionally lower alkyl or trifluorolower alkyl, may be performed by methods that are well known in the field of organic chemistry to give the compounds of structure 15. For example, in accordance with procedure (q) the thiooxamate of stucture 17 was treated with the halomethylketone of structure 16 in an inert solvent such as ethanol at a temperature of from room temperature to 78 degrees, preferably at about 78 degrees.
The condensation of the thioamide of structure 20, in which R14 represents for example amino, optionally branched lower alkyl or trifluoro lower alkyl with a 2-halo-3-oxocarboxylic acid ester of structure 19, where X represents bromo or chloro, preferably chloro and R14 is for example optionally branched lower alkyl or trifluoro lower alkyl may be performed by methods that are well known in the field of organic chemistry to give the compounds of structure 18. For example, accordance with procedure (r) the thioamide of structure 20 was treated with a 2-halo-3-oxocarboxylic acid ester of structure 19 in an inert solvent such as ethanol at a temperature of from room temperature to 78 degrees, preferably at about 78 degrees.
The compounds of structure 11, in which R10 represents for example an unbranched lower alkyl group (e.g., methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, may be prepared by any conventional means. For example, they may be prepared by 
(s) for the preparation of a compound of structure 11 in which A represents 
xe2x80x83by reacting a compound of structure 21 or a salt thereof with a compound of structure 22 or a reactive derivative thereof, or
(t) for the preparation of a compound of structure 11 in which A represents 
xe2x80x83by reacting a compound of structure 23 with a reactive derivative of a compound of structure 22 under reducing conditions, or
(u) for the preparation of a compound of structure 11 in which A represents 
xe2x80x83by reacting an isocyanate of structure 24 with an aniline of structure 25, and converting the resulting urea into an aminotetrazole, or
(v) for the preparation of a compound of structure 11 in which A represents 
xe2x80x83by reacting an isocyanate of structure 27 with an amine of structure 26, and converting the resulting urea into an aminotetrazole, or
(w) for the preparation of a compound of structure 11 in which A represents 
xe2x80x83by treating an aldehyde of structure 28 with a phosphorane of structure 29, and catalytically reducing the resulting chalcone, or
(x) for the preparation of a compound of structure 11 in which A represents 
xe2x80x83by treating an aldehyde of structure 28 with a phosphorane of structure 29, and selectively reducing the carbonyl function in the resulting chalcone,
The acylation of compounds of structure 21, in which R18 represents hydrogen or lower alkyl, to give compounds of structure 11, in which A represents 
in accordance with procedure (s) can be effected in a manner analogous to that described earlier in connection with the coupling of a compound of structure 5 with a compound of structure 6.
The coupling of compounds of structure 23, in which R18 represents hydrogen or lower alkyl, with reactive derivatives of compounds of structure 22 in accordance with procedure (t) can be carried out under conditions that are known per se. Examples of reactive derivatives of compounds of structure 22 that can be used in the reaction are acid anhydrides, mixed anhydrides, and activated esters (e.g., the N-hydroxysuccinimidyl ester), preferably activated esters. The reaction can be conveniently carried out using palladium-on-carbon as the reduction catalyst in the presence of hydrogen at a pressure between about 14 pounds per square inch and about 50 pounds per square inch, preferably about 14 pounds per square inch. The reaction may be conducted in the presence of an inert solvent such as ethyl acetate, or an aromatic hydrocarbon (e.g., benzene), or an alcohol (e.g., methanol), or in a mixture of such solvents. The reaction may be conveniently carried out at a temperature about room temperature.
The coupling of isocyanates of structure 24 with anilines of structure 25 to give ureas, in accordance with procedure (u), may be carried out by methods known per se. For example, the reaction may be carried out by reacting the isocyanate of structure 24 with the aniline of structure 25 or salt thereof in the presence of a suitable base, such as a tertiary amine (e.g., diisopropylethylamine), in an inert solvent such as an aromatic hydrocarbon (e.g., benzene). The reaction can be carried out conveniently at a temperature between about 80 degrees and about 110 degrees, preferably at about 80 degrees. Alternatively, the same urea can also be prepared by the coupling of isocyanates of structure 27 with amines of structure 26 in accordance with procedure (v). For example, the reaction may be carried out by reacting the isocyanate of structure 27 with the amine or amine salt of structure 26 in the presence of a suitable base, such as a tertiary amine (e.g., diisopropylethylamine), in an inert solvent such as an aromatic hydrocarbon (e.g., benzene). The reaction can be carried out conveniently at a temperature between about 80 degrees and about 110 degrees, preferably at about 80 degrees. The resulting urea can be converted to the aminotetrazole using any conventional means for effecting such a transformation, such as by treatment with trimethylsilylazide under dehydrating conditions. For example, the reaction can be conveniently carried out by treating the urea with trimethylsilylazide, diethylazodicarboxylate, and triphenylphosphine in an inert solvent, such as tetrahydrofuran, at a temperature between about zero degrees and about room temperature, preferably at about room temperature.
The coupling of aldehydes of structure 28 with phosphoranes of structure 29 to give chalcones, in accordance with procedure (w), may be carried out by methods that are well known in the field of organic chemistry. For example, the phosphorane may be treated with the aldehyde in an inert solvent such as an aromatic hydrocarbon (e.g., benzene) at a temperature between about 80 degrees and about 110 degrees, preferably at about 80 degrees. The resulting chalcone can be reduced by catalytic hydrogenation to give a compound of structure 11, in which A represents 
The reaction may be carried out by hydrogenation in the presence of a noble metal catalyst such as palladium-on-carbon in the presence of an inert solvent (for example, ethyl acetate or an alcohol such as ethanol) at about room temperature and under 1 atmosphere of hydrogen.
The coupling of aldehydes of structure 28 with phosphoranes of structure 29 to give chalcones, in accordance with procedure (x), may be carried out by methods that are well known in the field of organic chemistry. For example, the phosphorane may be treated is with the aldehyde in an inert solvent such as an aromatic hydrocarbon (e.g., benzene) at a temperature between about 80 degrees and about 110 degrees, preferably at about 80 degrees. The resulting chalcone can be reduced with a metal borohydride, for example sodium borohydride to give a compound of structure 11, in which A represents 
The reaction may be carried out in the presence of an inert solvent (for example, an alcohol such as methanol) at about room temperature.
The starting materials of structure 21, 25, and 26 are generally known compounds. 
Compounds of structure 16 are generally known compounds, or if they are not known compounds, they can be prepared by means which are well known to one of ordinary skill in the field. For example, in accordance with procedure (y), a methyl ketone of structure 30 in a lower unbranched alcohol (e.g., methanol) is treated with bromine. The reaction is conveniently carried out at a temperature between about xe2x88x925 degrees and about room temperature, preferably at zero degrees.
The thiooxamates of structure 17 are generally known compounds, or if they are not known compounds, they can be prepared by means that are well known in the field. For example, in accordance with procedure (z), an oxamic acid ester of structure 31 in an inert solvent such as an ether (e.g., tetrahydofuran) is treated with Lawesson""s Reagent. The reaction is conveniently carried out at a temperature between about room temperature and about 66 degrees, preferably at about 66 degrees.
Compounds of structure 19 are generally known compounds, or if they are not known compounds, they can be prepared by methods that are well known in the field. For example, in accordance with procedure (aa), a 3-oxocarboxylic acid ester of structure 32 in an inert solvent such as a chlorinated hydrocarbon (e.g., dichloromethane) is treated with sulfuryl chloride. The reaction is conveniently carried out at a temperature between about zero degrees and about room temperature, preferably at zero degrees.
The thioamides of structure 20 are generally known compounds, or if they are not known compounds , they can be prepared by methods that are well known in the field. For example, in accordance with procedure (bb), an amide of structure 33 in an inert solvent mixture such as a mixture of an ether (e.g., diethyl ether) and an aromatic hydrocarbon (e.g., benzene) is treated with phosphorous pentasulfide. The reaction is conveniently carried out at a temperature between about zero degrees and about 35 degrees, preferably at room temperature.
The starting materials of structure 30, 31, 32, and 33 are generally known compounds. Insofar as they are not known compounds or analogues of known compounds, they can be prepared in a similar manner to the known compounds or as described in the Examples hereinafter or in analogy thereto 
The compounds of structure 22 can be made by any conventional means. For example, they may be prepared by:
(cc) hydrolyzing a compound of structure 34 in which R10 and R15 separately represent an unbranched lower alkyl group (e.g., methyl or ethyl), an aralkyl group, or a tert-butyl group or the like, or
(dd) carboxylating a compound of structure 35, in which R16 is a group that can be substituted under noble metal catalysis, such as iodide, bromide, or trifluoromethanesulfonate.
The hydrolysis of compounds of structure 34 in accordance with procedure (cc) can be effected by any conventional means. For example, in the case of a compound of structure 34 in which R15 is a group that can be cleaved by basic hydrolysis, the reaction can be conveniently effected by treating the compound with one equivalent of an alkali metal hydroxide, such as potassium hydroxide, sodium hydroxide, or lithium hydroxide, preferably lithium hydroxide, in a suitable solvent, such as a mixture of tetrahydrofuran, methanol, and water. The reaction can be carried out at a temperature between about zero degrees and about room temperature, preferably at about room temperature.
The carboxylation of compounds of structure 35, in which R16 is a group that can be substituted under noble metal catalysis, such as iodide, bromide, or trifluoromethanesulfonate, in accordance with procedure (dd) can be carried out using conventional methods. For example, the reaction can be carried out by reacting the compound of structure 35 with water under carbon monoxide gas at a pressure between about 14 pounds per square inch and about 50 pounds per square inch, preferably at about 40 pounds per square inch, in the presence of a noble metal catalyst such as tetrakis(triphenylphosphine)palladium(0), allylpalladium(II) chloride dimer, or dichlorobis(triphenylphosphine)palladium(II), and a base, for example a tertiary amine, such as triethylamine, in an inert solvent, such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, or the like. The reaction can be carried out at a temperature between about 40 degrees and about 100 degrees, preferably at about 80 degrees.
Compounds of structure 23 may be prepared by any conventional means. For example, in the case where R18 is hydrogen, they may be prepared from compounds of structure 49 by substitution of the bromine. The reaction may be carried out by treating a compound of structure 49 with an alkali metal azide salt, preferably sodium azide, in the optional additional presence of an agent that will increase the rate of the reaction, such as potassium iodide. The reaction may be carried out in the presence of an inert solvent such as acetone or N,N-dimethylformamide at a temperature of between about room temperature and about 60 degrees, preferably at about 60 degrees. In the case where R18 is a lower alkyl group, or where compounds of structure 49 are not available due to the reactivity of the aromatic or heteroaromatic moiety, compounds of structure 23 may be prepared by reaction of an alcohol of structure 50, in which R18 represents hydrogen or lower alkyl, with a reagent such as diphenylphosphoryl azide. The reaction is conveniently carried out in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene and an inert solvent such as tetrahydrofuran at a temperature around room temperature.
Compounds of structure 21 where R18 is hydrogen may be made by methods that are known per se in the field of organic chemistry. For example, they may be made by the reduction of carbonitriles of structure 48. For example, in the case where the compound if of structure 21 is prepared by catalytic hydrogenation, a noble metal catalyst such as palladium-on-carbon may be used. The reaction may be carried out in the presence of a 1-2 molar ratio of a hydrohalic acid, preferably hydrochloric acid an inert solvent (for example, an alcohol such as ethanol) at about room temperature and under 1-4 atmospheres of hydrogen. 
Compounds of structure 24 or 27 can be prepared by reactions that are known per se. For example, they can be prepared by an in situ Curtius rearrangement of compounds of the structure 42 and structure 44 respectively. The reaction can be conveniently carried out by initially treating the compounds of structure 43 or structure 22 with a reagent such as diphenylphosphoryl azide and a base such as a tertiary amine (e.g., diisopropylethylamine) in an inert solvent such as an aromatic hydrocarbon (e.g., benzene) at a temperature of from zero degrees to about room temperature. The rearrangement of the thus formed thermally labile intermediate acyl azides of structures 42 and 44 into the compounds of structures 24 and 27 can be carried out conveniently at a temperature of around 70 degrees.
Compounds of structure 28 are generally known compounds, or if they are not known compounds, they can be prepared by methods that are well known to one of ordinary skill in the field. For example they can be prepared by oxidation of compounds of structure 50 in which R18 represents hydrogen by procedures analogous to those described above for the preparation of compounds of structure 4 by the oxidation of compounds of structure 8.
Compounds of structure 29 can be prepared by a variety of methods well known in the field of organic chemistry. For example, they can be prepared by deprotonation of the corresponding phosphonium salts by treatment with a base, for example sodium carbonate, in an inert solvent, such as a mixture of an aromatic hydrocarbon (e.g., benzene) and water. The reaction can conveniently be carried out at about room temperature. The phosphonium salts can be prepared by any conventional means. For example, they can be prepared by a substitution reaction of compounds of structure 45. The reaction may conveniently be carried out by treating a compound of structure 45 with triphenylphosphine in the optional presence of a catalytic amount of pyridine in an inert solvent such as acetonitrile. The reaction can be run at a temperature between about room temperature and about 80 degrees, preferably at about room temperature.
Compounds of structure 34 are generally known compounds, or if they are not known compounds, they can be prepared by any conventional means. For example, compounds of structure 34 can be prepared by esterification of compounds of structure 36. This reaction can be effected by methods that are well known to one of ordinary skill in the field. For example, a compound of structure 34, in which R10 represents methyl, can be prepared from a compound of structure 36 by reaction with an ethereal solution of diazomethane. The reaction is conveniently carried out in an inert solvent such as an ether (e.g., diethyl ether or tetrahydrofuran) or an alcohol (e.g., methanol), at a temperature of between about zero degrees and about room temperature, preferably at about zero degrees.
Compounds of structure 34 in which R4 and R5 both represent chlorine can be prepared from compounds of structure 55 by reactions that are well known. For example, in the case where R4 and R5 both represent chlorine, compounds of structure 34 can be prepared by reaction of compounds of structure 55 with a diazotizing reagent, preferably an alkyl nitrite, most preferably isoamyl nitrite, in a suitable solvent which can also act as a hydrogen donor, for example N,N-dimethylformamide or preferably tetrahydrofuran, at a suitable temperature, for example at about 65 degrees. 
Compounds of structure 36 can be prepared by reactions that are well known. For example, they can be made from the trifluoromethanesulfonate derivatives, structure 37, by reaction with carbon monoxide and water under noble metal catalysis. This reaction can be carried out in a manner analogous to that described earlier in connection with the carboxylation of compounds of structure 35.
Compounds of structure 37 can be prepared by reactions that are known per se. For example, they can be prepared by reacting compounds of structure 38 with a reactive derivative of trifluoromethanesulfonic acid, such as trifluoromethanesulfonic anhydride or N-phenyltrifluoromethanesulfonimide, preferably trifluoromethanesulfonic anhydride, in the presence of a base, such as a tertiary amine (e.g., diisopropylethylamine), in an inert solvent, such as halogenated hydrocarbon (e.g., dichloromethane). The reaction can be conveniently carried out between about xe2x88x9278 degrees and about room temperature, preferably at about xe2x88x9240 degrees.
Compounds of structure 38 can be prepared by any conventional means. For example, they can be prepared by esterifying compounds of structure 39 by a number of different reactions, such as those conventionally used to prepare esters of carboxylic acids, preferably by reactions that permit the esterification of the carboxylic acid in the presence of the phenolic hydroxyl group. For example, the compounds of structure 38, in which R15 represents methyl, can be prepared by treatment of compounds of structure 39 with a solution of methanol containing a strong inorganic acid, for example sulfuric acid or a hydrohalic acid such as hydrogen chloride. The reaction is conveniently carried out at a temperature between about room temperature and about 65 degrees, preferably at about room temperature. 
Compounds of structure 39 can be prepared by a variety of methods that are known in the field of organic chemistry. For example, they may be prepared by oxidation of compounds of structure 40. This oxidation can be carried out conveniently by treating the compound of structure 40 with an oxidizing agent such as sodium chlorite, in the optional presence of a scavenger of chlorine dioxide such as sulfamic acid. The reaction is conveniently carried out in an inert solvent system such as a mixture of water and tert-butanol, at a temperature between about zero degrees and about 50 degrees, preferably at about room temperature.
Compounds of structure 40 can be prepared by any conventional means. For example, they can be prepared from compounds of structure 41 by a variety of procedures, such as by treatment of the compound of structure 41 with hexamethylenetetramine under acidic conditions, for example by carrying out the reaction in an acidic solvent such as trifluoroacetic acid. The reaction is conveniently carried out at about 70 degrees. 
Compounds of structure 45 can be made by any conventional means. For example, such compounds can be made by reacting a diazoketone of structure 46 with hydrogen bromide. The reaction can be conveniently carried out by bubbling hydrogen bromide gas into a suspension of the compound of structure 46 in an inert solvent such as diethyl ether. The reaction may be carried out at a temperature between about zero degrees and about room temperature, preferably at about room temperature.
Compounds of structure 46 can be made by any conventional means. For example, they can be prepared by treating compounds of structure 47 with diazomethane. The reaction is conveniently carried out in the presence of a base, such as a tertiary amine (e.g., triethylamine) in an inert solvent such as diethyl ether at a temperature of between xe2x88x9210 degrees and about room temperature, preferably at about zero degrees.
Compounds of structure 47 can be made a variety of methods familiar to one of ordinary skill in the art. For example, they can be made by reaction of a compound of structure 22 with a reagent that is commonly used for the conversion of carboxylic acids to acid chlorides such as thionyl chloride or oxalyl chloride in the presence or absence of an inert solvent such as an aromatic hydrocarbon (e.g., benzene) or dichloromethane. In the case where thionyl chloride is used, the reaction can be carried out at a temperature of about 80 degrees. 
Compounds of structure 49, in which R18 represents hydrogen or lower alkyl, can be made by any conventional means. For example, in the case where R18 represents hydrogen, they may be made by bromination of compounds of structure 51 where the other functionalities in the structure may contain appropriate protective groups that will be apparent to one of ordinary skill in the art of organic synthesis. The bromination may be carried out by treatment of a compound of structure 51 with a brominating agent such as N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or bromine, preferably N-bromosuccinimide. The reaction may be carried out in the presence of an agent that will increase the rate of the reaction such as azodiisobutyronitrile or benzoyl peroxide, and/or under irradiation from a light source such as a low pressure mercury lamp. The reaction may be carried out in the presence of an inert solvent such as carbon tetrachloride, at a suitable temperature such as about 76 degrees.
Compounds of structure 50 are generally known compounds, or can be prepared in a similar manner to the known compounds. For example, the reduction of compounds of structure 52 to give compounds of structure 50 in which R18 represents hydrogen, in accordance with procedure (o) can be effected in a manner analogous to that described earlier in connection with the reduction of a compound of structure 9 to furnish a compound of structure 8. As a further example, compounds of structure 50 in which R18 represents methyl can be prepared from compounds of structure 28 by reaction with an organometallic reagent. This reaction can be conveniently carried out by adding a reagent such as methyllithium or methylmagnesium bromide to the compound of structure 28 in an inert solvent such as an ether (e.g., diethyl ether or tetrahydrofuran) at a temperature between about xe2x88x9278 degrees and about room temperature, preferably at about xe2x88x9278 degrees.
Compounds of structure 51 are generally known compounds. Insofar as they are not known compounds or analogues of known compounds, they can be prepared in a similar manner to the known compounds or as described in the Examples hereinafter or in analogy thereto.
Compounds of structure 52 are generally known compounds or can be made a variety of methods familiar to one of ordinary skill in the art. For example, the esterification of compounds of structure 53 to give compounds of structure 52 in which R17 represents lower alkyl, in accordance with procedure (p) can be done in a manner analogous to that described earlier in connection with the esterification of a compound of structure 14 to furnish a compound of structure 9.
Compounds of structure 53 are generally known compounds. Insofar as they are not known compounds or analogues of known compounds, they can be prepared in a similar manner to the known compounds or as described in the Examples hereinafter or in analogy thereto. 
Compounds of structure 55 can be made by any conventional means. For example, compounds of structure 55 can be made by chlorination of compounds of structure 54, for example by treatment with a chlorinating agent such as N-chlorosuccinimide in a polar solvent such as acetonitrile at a suitable temperature, such as at around 65 degrees. Compounds of structure 54 are generally known compounds, or can be prepared in a similar manner to the known compounds.